A Sterol-Binding Protein Integrates Endosomal Lipid Metabolism with TOR Signaling and Nitrogen Sensing

Mousley, Carl J.; Yuan, Peihua; Gaur, Naseem A.; Trettin, Kyle D.; Nile, Aaron H.; Deminoff, Stephen J.; Dewar, Brian; Wolpert, Max; Macdonald, Jeffrey M.; Herman, Paul K.; Hinnebusch, Alan G.; Bankaitis, Vytas A.

doi:10.1016/j.cell.2011.12.026

Cited by 84 publications

(115 citation statements)

References 39 publications

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“…In yeast, where the type II PI4K homolog Lsb6p is not a major Golgi regulator, the Golgi recruitment of all of the OSH proteins studied were dependent on Pik1p (1783). Moreover, the unique OSBP homolog Kes1p, the deletion of which alleviates the need for the PI transfer protein Sec14p (902), has a complex sterol-regulated antagonistic relationship with TGN/endosomal PtdIns4P signaling (1089). Recent studies have shown that Kes1p (also called Osh4p) exchanges sterols picked up from the ER for PtdIns4P at the Golgi membrane and, hence, the Golgi PtdIns4P made by Pik1p drives Kes1p-mediated sterol transport between the ER and Golgi membranes (339).…”

Section: B Golgimentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,365

1,655

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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Section: B Golgimentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,365

1,655

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“…Many physiological processes, including cell migration, angiogenesis, metabolism and development, depend on proper functioning of endocytosis and thus cells have developed multiple mechanisms to ensure proper intracellular trafficking and endocytosis (Fernández-Rojo et al, 2012;Gu et al, 2011;Lee et al, 2014;Mousley et al, 2012;Parachoniak et al, 2011). There are multiple pathways of endocytosis into cells, including, clathrindependent, caveolin-dependent and clathrin-and caveolinindependent internalization.…”

Section: Introductionmentioning

confidence: 99%

The miR-199/DNM regulatory axis controls receptor-mediated endocytosis

Aranda

Canfrán‐Duque

Goedeke

et al. 2015

Journal of Cell Science

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Small non-coding RNAs (microRNAs) are important regulators of gene expression that modulate many physiological processes; however, their role in regulating intracellular transport remains largely unknown. Intriguingly, we found that the dynamin (DNM) genes, a GTPase family of proteins responsible for endocytosis in eukaryotic cells, encode the conserved miR-199a and miR-199b family of miRNAs within their intronic sequences. Here, we demonstrate that miR-199a and miR-199b regulate endocytic transport by controlling the expression of important mediators of endocytosis such as clathrin heavy chain (CLTC), Rab5A, lowdensity lipoprotein receptor (LDLR) and caveolin-1 (Cav-1). Importantly, miR-199a-5p and miR-199b-5p overexpression markedly inhibits CLTC, Rab5A, LDLR and Cav-1 expression, thus preventing receptor-mediated endocytosis in human cell lines (Huh7 and HeLa). Of note, miR-199a-5p inhibition increases target gene expression and receptor-mediated endocytosis. Taken together, our work identifies a new mechanism by which microRNAs regulate intracellular trafficking. In particular, we demonstrate that the DNM, miR-199a-5p and miR-199b-5p genes act as a bifunctional locus that regulates endocytosis, thus adding an unexpected layer of complexity in the regulation of intracellular trafficking.

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“…The elongation process appears to be overdetermined (Mason and Struhl 2005), such that only a few specialized genes require a full complement of cofactors for efficient transcription elongation in vivo (Chavez et al 2001). Whereas the elongation defect described here likely applies broadly to many genes, the impairment of transcription initiation we observed previously in vps mutants (Zhang et al 2008) is restricted to a subset of activators that includes Gcn4, but not Gal4, and seems to involve a signaling pathway that responds to sterol limitation (Mousley et al 2012). Hence, we now interpret the dramatic reductions in expression of Gcn4-dependent lacZ reporters we observed previously in vps15D and vps34D mutants (Zhang et al 2008) to be the compound effect of reduced PIC assembly by Gcn4 and impaired transcription elongation through lacZ CDS.…”

Section: Discussionmentioning

confidence: 70%

“…More recently, evidence was provided that sterol limitation also down-regulates Gcn4 function in the nucleus, in a manner involving sterol binding protein Kes1 and its ability to inhibit PI(4)P-directed vesicular protein trafficking with an attendant increase in cellular sphingolipids. It appears that elevated sphingolipids provoke a reduction in Gcn4 function in a manner involving the CDK8 module of the transcriptional coactivator Mediator complex (Mousley et al 2012).…”

mentioning

confidence: 99%

Vps Factors Are Required for Efficient Transcription Elongation in Budding Yeast

et al. 2013

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There is increasing evidence that certain Vacuolar protein sorting (Vps) proteins, factors that mediate vesicular protein trafficking, have additional roles in regulating transcription factors at the endosome. We found that yeast mutants lacking the phosphatidylinositol 3-phosphate [PI(3)P] kinase Vps34 or its associated protein kinase Vps15 display multiple phenotypes indicating impaired transcription elongation. These phenotypes include reduced mRNA production from long or G+C-rich coding sequences (CDS) without affecting the associated GAL1 promoter activity, and a reduced rate of RNA polymerase II (Pol II) progression through lacZ CDS in vivo. Consistent with reported genetic interactions with mutations affecting the histone acetyltransferase complex NuA4, vps15D and vps34D mutations reduce NuA4 occupancy in certain transcribed CDS. vps15D and vps34D mutants also exhibit impaired localization of the induced GAL1 gene to the nuclear periphery. We found unexpectedly that, similar to known transcription elongation factors, these and several other Vps factors can be cross-linked to the CDS of genes induced by Gcn4 or Gal4 in a manner dependent on transcriptional induction and stimulated by Cdk7/Kin28-dependent phosphorylation of the Pol II C-terminal domain (CTD). We also observed colocalization of a fraction of Vps15-GFP and Vps34-GFP with nuclear pores at nucleus-vacuole (NV) junctions in live cells. These findings suggest that Vps factors enhance the efficiency of transcription elongation in a manner involving their physical proximity to nuclear pores and transcribed chromatin. N EWLY synthesized proteins that are transported from the Golgi to the lysosome/vacuole traverse the endosome, as do ubiquitinated proteins that are removed from the plasma membrane by endocytosis en route to the vacuole for degradation. Ubiquitinated cargo proteins progress through early and late endosomes, are concentrated at the outer membranes of multivesicular bodies (MVB), and are then sequestered in intralumenal vesicles (ILVs) It is thought that ESCRT-0 is recruited from the cytoplasm to the endosomal outer membrane by interaction with the phosphoinositide PI(3)P, where it acts to recruit and concentrate ubiquitinated cargo proteins and transfer them to the ESCRT-I complex. ESCRT-I activates the ESCRT-II heterotrimer that, in turn, recruits the ESCRT-III components, which are believed to assemble filaments instrumental in invagination of the MVB membrane. The AAA-ATPase Vps4, recruited by ESCRT-III subunits, functions to pinch off the membrane invaginations to produce ILVs containing cargo proteins and to recycle the ESCRT factors back to the cytoplasm (Raiborg and Stenmark 2009).

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A Sterol-Binding Protein Integrates Endosomal Lipid Metabolism with TOR Signaling and Nitrogen Sensing

Cited by 84 publications

References 39 publications

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

The miR-199/DNM regulatory axis controls receptor-mediated endocytosis

Vps Factors Are Required for Efficient Transcription Elongation in Budding Yeast

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